A carboxy-terminal ubiquitylation site regulates androgen receptor activity

作者全名："Arai, Seiji; Gao, Yanfei; Yu, Ziyang; Xie, Lisha; Wang, Liyang; Zhang, Tengfei; Nouri, Mannan; Chen, Shaoyong; Asara, John M.; Balk, Steven P."

作者地址："[Arai, Seiji; Gao, Yanfei; Yu, Ziyang; Xie, Lisha; Wang, Liyang; Zhang, Tengfei; Nouri, Mannan; Chen, Shaoyong; Asara, John M.; Balk, Steven P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA; [Arai, Seiji; Gao, Yanfei; Yu, Ziyang; Xie, Lisha; Wang, Liyang; Zhang, Tengfei; Nouri, Mannan; Chen, Shaoyong; Asara, John M.; Balk, Steven P.] Harvard Med Sch, Canc Ctr, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA; [Arai, Seiji] Gunma Univ Hosp, Dept Urol, Maebashi, Gunma, Japan; [Gao, Yanfei] Chongqing Med Univ, Sch Basic Med Sci, Chongqing 400016, Peoples R China"

通信作者："Balk, SP (通讯作者)，Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.; Balk, SP (通讯作者)，Harvard Med Sch, Canc Ctr, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA."

来源：COMMUNICATIONS BIOLOGY

ESI学科分类：　

WOS号：WOS:001137134800008

JCR分区：Q1

影响因子：5.9

年份：2024

卷号：7

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition, but this is associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases. We then identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methylation sites and previously identified phosphorylation sites. Mutagenesis of K911 increases AR stability, chromatin binding, and transcriptional activity. We further found that K313, a previously reported ubiquitylation site, could also be methylated and acetylated. Mutagenesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications at K313 differentially regulate AR activity. Together these studies expand the spectrum of AR posttranslational modifications, and indicate that the K911 site may regulate AR turnover on chromatin. Extensive mutagenesis and molecular investigation of the unliganded androgen receptor (AR) expands the known spectrum of AR post-translational modifications, including a ubiquitylation site at p.K911 that may regulate AR turnover on chromatin."

基金机构："U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) [W81XWH-13-1-0254, W81XWH-14-1-0245]; Department of Defense (DoD) Prostate Cancer Research Program Postdoctoral Training Awards [W81XWH-13-1-0266]; DoD Prostate Cancer Research Program Idea Development Award [P50 CA090381, P01 CA163227, P01 CA120964]; DF/HCC-Prostate Cancer SPORE; Gunma University Hospital; Prostate Cancer Foundation Challenge Award"

基金资助正文："We thank Susanne Breitkopf for assistance with LC/MS/MS. This study was supported by Department of Defense (DoD) Prostate Cancer Research Program Postdoctoral Training Awards to Z.Y. (W81XWH-13-1-0254) and Y.G. (W81XWH-14-1-0245), DoD Prostate Cancer Research Program Idea Development Award to S.P.B/ (W81XWH-13-1-0266), DF/HCC-Prostate Cancer SPORE P50 CA090381 (S.P.B.), NIH P01 CA163227 (S.P.B.), NIH P01 CA120964 (J.M.A.), a Research Fellowship from Gunma University Hospital (S.A.), and Prostate Cancer Foundation Challenge Award (S.P.B.)."